17-41118057-G-A

Variant names:

• chr17-41118057-G-A
• rs769807463
• NM_033059.4:c.259C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033059.4(KRTAP4-11):​c.259C>T​(p.Pro87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,526,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KRTAP4-11 NM_033059.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.134
• Publications: 0 publications found

Genes affected

KRTAP4-11 (HGNC:18911): (keratin associated protein 4-11) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Mar 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10765135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-11	NM_033059.4	MANE Select	c.259C>T	p.Pro87Ser	missense	Exon 1 of 1	NP_149048.2	Q9BYQ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-11	ENST00000391413.4	TSL:6 MANE Select	c.259C>T	p.Pro87Ser	missense	Exon 1 of 1	ENSP00000375232.2	Q9BYQ6

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247724 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000116 AC: 16 AN: 1378060 Hom.: 0 Cov.: 223 AF XY: 0.0000117 AC XY: 8 AN XY: 681816

African (AFR) AF: 0.00 AC: 0 AN: 30380

American (AMR) AF: 0.00 AC: 0 AN: 40138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24036

East Asian (EAS) AF: 0.00 AC: 0 AN: 36816

South Asian (SAS) AF: 0.00 AC: 0 AN: 72716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5282

European-Non Finnish (NFE) AF: 0.0000150 AC: 16 AN: 1063492

Other (OTH) AF: 0.00 AC: 0 AN: 55970

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72414

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38044

American (AMR) AF: 0.00 AC: 0 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67890

Other (OTH) AF: 0.00 AC: 0 AN: 2036

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000833 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.71
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.13
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.045
Sift	Benign	0.071	T
Sift4G	Benign	0.091	T
Polyphen		0.0040	B
Vest4		0.14
MutPred		0.48		Loss of loop (P = 0.1242)
MVP		0.12
MPC		0.0087
ClinPred		0.067	T
GERP RS		0.70
PromoterAI		0.0036	Neutral
Varity_R		0.067
gMVP		0.066
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769807463; hg19: chr17-39274309;